Abstract
Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of Mycobacterium tuberculosis cytochrome bcc alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. M. tuberculosis cytochrome bcc forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol-binding pockets. We observe Q203 and TB47 bound at the quinol-binding site and stabilized by hydrogen bonds with the side chains of QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.
Highlights
Mycobacteria, which belong to the phylum Actinobacteria, have coevolved with humans over thousands of years (Chisholm et al, 2016)
Structure of M. tuberculosis cytochrome bcc Considering that the hybrid supercomplex
The study shows the structural features of M. tuberculosis cytochrome bcc and how it is inhibited by Q203 and TB47
Summary
Mycobacteria, which belong to the phylum Actinobacteria, have coevolved with humans over thousands of years (Chisholm et al, 2016). Most mycobacteria are saprophytes or non- pathogenic to humans, a few species cause diseases, resulting in pulmonary and extra-p ulmonary infections that can affect most organs. Infections involving other pathogenic mycobacteria, for example, Mycobacterium abscessus and Mycobacterium avium complex, are on the rise with some outnumbering those caused by M. tuberculosis in countries including the United States (Donohue, 2018; Johansen et al, 2020). These infections are notoriously difficult to treat due to intrinsic or emerging resistance to many common antibiotics, exacerbating the challenge to find suitable drug targets. These high-resolution structures will greatly accelerate efforts towards structure-guided drug discovery
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